Chemotherapy-induced peripheral neuropathy (CIPN) is a

nerve A nerve is an enclosed, cable-like bundle of nerve fibers (called axons) in the peripheral nervous system. A nerve transmits electrical impulses. It is the basic unit of the peripheral nervous system. A nerve provides a common pathway for the e ...

-damaging side effect of antineoplastic agents in the common

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

treatment,

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

. CIPN afflicts between 30% and 40% of patients undergoing chemotherapy. Antineoplastic agents in chemotherapy are designed to eliminate rapidly dividing cancer cells, but they can also damage healthy structures, including the

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...

. CIPN involves various symptoms such as tingling, pain, and numbness in the hands and feet. These symptoms can impair activities of daily living, such as typing or dressing, reduce balance, and increase risk of falls and hospitalizations. They can also give cause to reduce or discontinue chemotherapy. Researchers have conducted

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

s and studies to uncover the various symptoms, causes,

pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...

, diagnoses, risk factors, and treatments of CIPN.

Symptoms and signs

CIPN symptoms manifest themselves as deficits in sensory,

motor An engine or motor is a machine designed to convert one or more forms of energy into mechanical energy. Available energy sources include potential energy (e.g. energy of the Earth's gravitational field as exploited in hydroelectric power gen ...

, and/or autonomic functions of varying intensity, and they can significantly reduce a patient's functional quality of life. Sensory symptoms affecting the hands and feet generally develop first. Sensory side effects are caused when nerves in the most distal parts of the limbs are damaged. Patients may experience numbness, tingling, altered touch sensation, gait and balance disturbances, burning pain, thermal

allodynia Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, bad sunburn can cause temporary allodynia, and touching sunburned skin, or running cold or warm water over it, can be very painful. It i ...

hyperalgesia Hyperalgesia ( or ; 'hyper' from Greek ὑπέρ (huper, “over”), '-algesia' from Greek algos, ἄλγος (pain)) is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and can ...

, impaired vibration sense, extreme temperature sensitivity,

paresthesia Paresthesia is an abnormal sensation of the skin (tingling, pricking, chilling, burning, numbness) with no apparent physical cause. Paresthesia may be transient or chronic, and may have any of dozens of possible underlying causes. Paresthesias ar ...

, and/or

dysesthesia Dysesthesia is an unpleasant, abnormal sense of touch. Its etymology comes from the Greek word "dys," meaning "bad," and "aesthesis," which means "sensation" (abnormal sensation). It often presents as pain On the other hand, motor symptoms are less frequently seen as sensory symptoms. Motor symptoms of CIPN can include cramping, distal weakness, difficulty handling small objects, and impaired movements. In severe cases, motor symptoms can lead to complete immobilization and severe disability. Finally, autonomic symptoms usually involve

orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up or sitting down. Primary orthostatic hypertension is also often referred to as neurogenic orthostatic hyp ...

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

, and altered urinary function. A patient experiencing CIPN symptoms may have difficulty performing daily functionalities like walking, dressing themselves, writing, typing, and other activities related to the hands and feet. The prevalence of these symptoms is highest in the first month after the completion of chemotherapy at 68.1%, but as many as 30% of patients still report CIPN symptoms six months after the completion of chemotherapy.

Paclitaxel Paclitaxel (PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer. This includes ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer ...

and

oxaliplatin Oxaliplatin, sold under the brand name Eloxatin among others, is a cancer medication (platinum-based antineoplastic class) used to treat colorectal cancer. It is given by injection into a vein. Common side effects include numbness, feeling ti ...

, representatives from two of the six major antineoplastic agents causing CIPN, cause

acute Acute may refer to: Science and technology * Acute angle ** Acute triangle ** Acute, a leaf shape in the glossary of leaf morphology * Acute (medicine), a disease that it is of short duration and of recent onset. ** Acute toxicity, the adverse eff ...

neuropathy, which manifests during or immediately after treatment infusion. The other four groups of agents generally cause late symptoms that emerge weeks after the completion of chemotherapy. In both cases, the severity of the symptoms are generally proportional to the dose of the treatment drug received, and the severity of the symptoms may warrant a reduction in the chemotherapy dosage. Pain and sensory abnormalities can persist for months or years after treatment completion. Some patients may experience “coasting,” where symptoms intensify after completion of treatment. As such, patients can be cancer-free and still suffer from disabling neuropathy induced by cancer treatment.

Causes

There are six main agent groups found in chemotherapy treatment that damage the sensory, motor, and autonomic neurons and therefore cause CIPN: 1) platinum-based compounds 2)

taxane Taxanes are a class of diterpenes. They were originally identified from plants of the genus ''Taxus'' (yews), and feature a taxadiene core. Paclitaxel (Taxol) and docetaxel (Taxotere) are widely used as chemotherapy agents. Cabazitaxel was FDA ap ...

s 3)

vinca alkaloid ''Vinca'' alkaloids are a set of anti-mitotic and anti-microtubule alkaloid agents originally derived from the periwinkle plant ''Catharanthus roseus'' (basionym ''Vinca rosea'') and other ''vinca'' plants. They block beta-tubulin polymerizatio ...

s 4)

epothilone Epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials, epothilones have better efficacy and milder adverse effects than taxanes. , epothilones A t ...

s 5)

proteasome inhibitor Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins. They are being studied in the treatment of cancer; and three are approved for use in treating multiple myeloma. Mechanism Multipl ...

s 6) immunomodulatory drugs. The mechanisms, side effects, and symptom duration for each of these groups are summarized below. 1) Platinum-based compounds, namely

cisplatin Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, br ...

, and

carboplatin Carboplatin, sold under the trade name Paraplatin among others, is a chemotherapy medication used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It is used b ...

(which is noticeably less neurotoxic than cisplatin), are used to treat several types of solid

tumors A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

, such as

stomach The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...

ovarian The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

, and

uterine The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the hollow organ, organ in the female reproductive system, reproductive system of most female mammals, including humans that accommodates the embryonic development, embryonic an ...

cancers. These agents can damage

dorsal root ganglia A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the do ...

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

s by forming

adduct An adduct (from the Latin ''adductus'', "drawn toward" alternatively, a contraction of "addition product") is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all co ...

s with

nuclear Nuclear may refer to: Physics Relating to the nucleus of the atom: * Nuclear engineering *Nuclear physics *Nuclear power *Nuclear reactor *Nuclear weapon *Nuclear medicine *Radiation therapy *Nuclear warfare Mathematics *Nuclear space *Nuclear ...

and

mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...

DNA. This damage can cause neuronal

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

, programmed cell death, which leads to neuropathy. Additionally, functional neuronal deficits have been identified, independent of structural damage, e.g. ion channelopathy, impaired spike encoding in the

central Central is an adjective usually referring to being in the center of some place or (mathematical) object. Central may also refer to: Directions and generalised locations * Central Africa, a region in the centre of Africa continent, also known as ...

and

. Specific side effects of platinum compounds include hearing loss,

tinnitus Tinnitus is the perception of sound when no corresponding external sound is present. Nearly everyone experiences a faint "normal tinnitus" in a completely quiet room; but it is of concern only if it is bothersome, interferes with normal hearin ...

, and dysesthesia. These symptoms generally begin with the or third cycle of treatment and can last long after treatment completion. Indeed, the “coasting” phenomenon mentioned in the ''Symptoms'' section is a direct effect of platinum agents. Of the platinum compounds, research has shown cisplatin to be the most frequently involved in peripheral neuropathy. 2) Taxanes, including paclitaxel (and protein-bound pactiltaxel e.g. abraxane),

docetaxel Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-ce ...

, and

cabazitaxel Cabazitaxel, sold under the brand name Jevtana, is a semi-synthetic derivative of a natural taxoid. It is a microtubule inhibitor, and the fourth taxane to be approved as a cancer therapy. Cabazitaxel was developed by Sanofi-Aventis and was ap ...

, are used to treat ovarian,

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and secret ...

, non-small cell lung, and

prostate The prostate is both an Male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, ...

cancers. These drugs interfere with the normal cycling of

microtubule Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...

depolymerization Depolymerization (or depolymerisation) is the process of converting a polymer into a monomer or a mixture of monomers. This process is driven by an increase in entropy. Ceiling temperature The tendency of polymers to depolymerize is indicated by ...

and repolymerization in small diameter sensory fibers to create sensory dominant neuropathy. Sensory side effects include paresthesias, dysesthesias, numbness, altered

proprioception Proprioception ( ), also referred to as kinaesthesia (or kinesthesia), is the sense of self-movement, force, and body position. It is sometimes described as the "sixth sense". Proprioception is mediated by proprioceptors, mechanosensory neurons ...

, and loss of

dexterity Fine motor skill (or dexterity) is the coordination of small muscles in movement with the eyes, hands and fingers. The complex levels of manual dexterity that humans exhibit can be related to the nervous system. Fine motor skills aid in the growt ...

in fingers and toes. Motor and autonomic symptoms are less frequent but possible. Symptoms may start days after the patient receives their first dose of chemotherapy, are dose dependent, and tend to improve after completion of treatment. However, in some cases, symptoms can persist six months or later following the completion of chemotherapy. Of the taxanes, paclitaxel has the most intense symptoms that may last for the longest time. 3) Vinca alkaloids, including

vincristine Vincristine, also known as leurocristine and marketed under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's ...

vinblastine Vinblastine (VBL), sold under the brand name Velban among others, is a chemotherapy medication, typically used with other medications, to treat a number of types of cancer. This includes Hodgkin's lymphoma, non-small cell lung cancer, bladder ca ...

vinorelbine Vinorelbine (NVB), sold under the brand name Navelbine among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer and non-small cell lung cancer. It is given by injection into a vein or by mou ...

, and

vindesine Vindesine, also termed Eldisine, is a semisynthetic vinca alkaloid derived from the flowering plant ''Catharanthus roseus.'' Like the natural (e.g. vinblastine and vincristine) and semisynthetic vinca alkaloids (e.g. vinorelbine and vinflunine) ...

, are used to treat tumors such as

Hodgkin lymphoma Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patient's lymph nodes. The condition wa ...

testicular cancer Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system. Symptoms may include a lump in the testicle, or swelling or pain in the scrotum. Treatment may result in infertility. Risk factors include an u ...

, and non-small cell lung cancer. These drugs inhibit the assembly of microtubules and thus disrupt

axonal transport Axonal transport, also called axoplasmic transport or axoplasmic flow, is a cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the cytoplas ...

in the cell body of peripheral nerves. Vinca alkaloids induce sensorimotor neuropathy, decreased sensation, in the hands and feet. Symptoms of vinca alkaloids include muscle weakness, initial pain after receiving an infusion, and cramping. These symptoms usually appear within the first three months of treatment. Of the vinca alkaloids, the most neurotoxic drug is vincristine. Vincristine disrupts the microtubular axonal transport system, which induces axonal neuropathy, distal numbness and tingling, and pain. 4) Epothilones, mainly

ixabepilone Ixabepilone (INN; also known as azaepothilone B, codenamed BMS-247550) is a pharmaceutical drug developed by Bristol-Myers Squibb as a chemotherapeutic medication for cancer. History Ixabepilone is a semi-synthetic analog of epothilone B, a natura ...

, are relatively new drugs that can be used to treat non-small lung, ovarian, and prostate cancers. Epothilones cause microtubule disruption (like taxane-based drugs), which impairs axonal transport and leads to hyperexcitability of peripheral neurons. They can cause neuropathy characterized by paresthesias, numbness, and pain in the hands and feet. Sensory and motor symptoms are commonly seen in patients treated with epothilone, which generally results in muscle weakness, while autonomic symptoms are rarely seen. The symptoms of this drug occur during treatment and tend to stop after completion. As of 2019, epothilones are not approved by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

for patient usage and are generally used only for patients not responding to other available chemotherapies. 5) Proteasome inhibitors, namely

bortezomib Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is ...

, are used in the treatment of

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...

and certain types of

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...

. Bortezomib increases the production of sphingosine-1 phosphate,

tumor necrosis factor α Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

, and interleukin-1β, which ultimately leads to the development of neuropathic pain. The side effects of receiving bortezomib include chronic, distal, and symmetrical sensory peripheral neuropathy and neuropathic pain syndrome which may last for weeks, months, or years after treatment completion. 6) Immunomodulatory drugs, mainly

thalidomide Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications of ...

, are used to treat multiple myeloma. The anticancer mechanism of these drugs are not completely understood, but they are believed to accelerate neuronal cell death and block

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

. Side effects of thalidomide-induced peripheral neuropathy include sensory symptoms, possible motor impairment, and

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

and

cardiovascular The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

autonomic manifestations. The symptoms of immunomodulatory drugs may dictate whether treatment is continued or discontinued, and they can last long-term after chemotherapy completion.

Risk factors

There are various factors that appear to predict the development of CIPN symptoms. Genetically, there are currently multiple

single nucleotide polymorphisms In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...

potentially associated with CIPN, as identified through the Genome Wide Association Studies. The reported polymorphisms are associated with a range of protein including voltage-gated

sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...

Schwann cell Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensh ...

function-related proteins, receptors for cell surface

collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...

, receptors involved in neuronal apoptosis, neuronal crest cell development, and an enzyme involved in

pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic aci ...

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

. Additionally, there are various diagnoses that may increase a patient's risk of developing CIPN: 1) A history with acquired or

hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic inform ...

neuropathy from

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

renal disease Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can b ...

hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...

connective tissue Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...

disease, or

vitamin A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an Nutrient#Essential nutrients, essential micronutrient that an organism needs in small quantities for the proper functioning of its ...

deficiencies is a risk factor. 2) A diagnosis of current or previous infectious disease such as

Human Immunodeficiency Virus The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause AIDS, acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the ...

Polio Poliomyelitis, commonly shortened to polio, is an infectious disease caused by the poliovirus. Approximately 70% of cases are asymptomatic; mild symptoms which can occur include sore throat and fever; in a proportion of cases more severe s ...

myelitis, and

Hepatitis B Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. Fo ...

or C may increase a patient's risk. 3) Exposure to medications linked to

neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...

, such as

cyclosporine Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease ...

vancomycin Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, ...

, and

cimetidine Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. The development of longer-acting H2 rec ...

, in the treatment of a previous diagnosis. There are also personal and treatment characteristics that may be potential risk factors: 1) Older age 2) Chemotherapy type 3) Cumulative dosage of chemotherapy treatment 4) Smoking history 5) History of alcohol intake 6) Dietary history 7) Race 8) Gender 9) Inactive lifestyle. In particular, the cumulative dosage of chemotherapeutic agents is a well-recognized risk factor of CIPN.

Diagnosis

Evaluation of a patient's medical history for the risk factors listed above is essential in the assessment of CIPN because CIPN symptoms may overlap with other

comorbid In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary c ...

conditions. Furthermore, the heterogeneity of CIPN means that patients describe their neuropathic symptoms in different ways. Some may report the impact of neuropathy in their daily life (e.g. difficulty with buttons, dropping objects, difficulty walking, etc.), and others might report traditional distal extremity numbness, burning, or pain. To assess the impact of symptoms on a patient's quality of life, clinicians currently use the Quality of Life Questionnaire-CIPN twenty item scale (CIPN-20) developed by the European Organization for Research and Treatment of Cancer. The CIPN-20 asks patients to rate their experience with different symptoms during a given period of time using scores from 1 (“not at all”) to 4 (“very much”). The results provide clinicians with critical information on a patient's functional limitations in relation to their exposure to potentially neurotoxic chemotherapeutic agents. In addition to the CIPN-20, the clinical Total Neuropathy Score for CIPN (TNS-c) can also be used to assess neuropathy signs and symptoms. The TNS-c has shown to be highly accurate in scoring the severity of CIPN, especially how it changes. Physical examination to assess

motor function Motor control is the regulation of movement in organisms that possess a nervous system. Motor control includes reflexes as well as directed movement. To control movement, the nervous system must integrate multimodal sensory information (both ...

, reflexes,

gait Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency. Di ...

and balance, and sensation also plays a key role in the diagnosis of CIPN. First, motor testing involves assessment of muscle tone and bulk, which may be decreased in patients with CIPN due to

atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...

and

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...

. Commonly affected muscle groups to look out for include the distal muscles of the hands, feet, and ankles. Second, a patient's reflexive response should be tested. The reflexes of patients with CIPN are frequently diminished, if not gone entirely. Dysfunction of the

Achilles reflex The ankle jerk reflex, also known as the Achilles reflex, occurs when the Achilles tendon is tapped while the foot is dorsiflexed. It is a type of stretch reflex that tests the function of the gastrocnemius muscle and the nerve that supplies it. ...

is especially common. Third, gait testing includes testing a patient's ability to walk on their heels and toes. Patients with distal foot weakness, a symptom of CIPN, may be unable to walk on their heels and commonly drag their toes while walking. The

Romberg sign Romberg's test, Romberg's sign, or the Romberg maneuver is a test used in an exam of neurology, neurological function for balance, and also as a test for driving under the influence of an intoxicant. The exam is based on the premise that a perso ...

should also be tested to indicate a patient's sense of balance. If patients are unable to stand with their feet together and their eyes closed,

proprioceptive Proprioception ( ), also referred to as kinaesthesia (or kinesthesia), is the sense of self-movement, force, and body position. It is sometimes described as the "sixth sense". Proprioception is mediated by proprioceptors, mechanosensory neurons ...

loss, commonly seen with CIPN, can be assumed. Finally, sensory testing should include the assessment of pain, vibration, and position sense. With their eyes closed, patients will be subjected to various stimuli to test their sensation. Pain can be tested with sharp stimulus such as a pin or a toothpick. Patients with CIPN may report objective numbness,

dysesthesia Dysesthesia is an unpleasant, abnormal sense of touch. Its etymology comes from the Greek word "dys," meaning "bad," and "aesthesis," which means "sensation" (abnormal sensation). It often presents as pain Vibratory sensation can be tested using a tuning fork applied to distal interphalangeal joints in the fingers and toes. Patients with CIPN commonly report vibratory sensation lasting less than eight seconds of absent vibration. Position sense can be tested by having a patient close his or her eyes with an examiner moving a distal joint up or down. Patients with CIPN will often be unable to correctly determine the direction of movement. In addition to examination of neurological symptoms, analysis of the administered drugs, the cumulative dosage, and the clinical characteristics and duration of the neuropathic symptoms are also important in the diagnosis of CIPN. First, clinicians must consider if the patient received a neurotoxic chemotherapeutic known to induce CIPN, such as the drugs from the six main groups mentioned above (i.e. platinum-based compounds,

s, and immunomodulatory drugs). It is also important to consider the route of drug administration because there are some drugs that may not be associated with neurotoxicity, unless administered through a certain route. For example, methotrexate is rarely correlated with neurotoxicity except when administered intrathecally, and bortezomib neurotoxicity can decrease with subcutaneous administration. Second, the drug dose the patient received, and if its amount is commensurate with developing CIPN, must be considered. The immunomodulatory drug bortezomib, for example, is more likely to cause neurotoxicity in a cumulative dose of 20 grams. Finally, the characteristics and the duration of a patient's symptoms should be analyzed. The onset of symptoms during or close after chemotherapy is generally described as affecting sensation in the feet first, then in the hands and fingers. If a patient experiences such abnormalities in sensation, then CIPN should be suspected. Furthermore, most CIPN symptoms appear during the first two months of treatment, progress during treatment, and stabilize after completion. It would be unexpected for CIPN to first appear weeks or months after the last dose of chemotherapy treatment. In CIPN,

sudomotor Sudomotor function refers to the autonomic nervous system control of sweat gland activity in response to various environmental and individual factors. Sweat production is a vital thermoregulatory mechanism used by the body to prevent heat-related ...

function, through elctrochemical skin conductance allows for an objective quantification of small fiber impairment and is easy to implement in the clinic.

Treatment and prevention

Pharmacological

Prevention

A 2020

American Society of Clinical Oncology The American Society of Clinical Oncology (ASCO) is a professional organization representing physicians of all oncology sub-specialties who care for people with cancer. Founded in 1964 by Fred Ansfield, Harry Bisel, Herman Freckman, Arnoldus G ...

(ASCO) report provided an updated list of drugs tested and NOT recommended for prevention of CIPN. These recommendations are evidence-based, informed by randomized trials, and guided by expert clinical experience. *

Acetyl-L-carnitine Acetyl-L-carnitine, ALCAR or ALC, is an acetylated form of L-carnitine. It is naturally produced by the human body, and it is available as a dietary supplement. Acetylcarnitine is broken down in the blood by plasma esterases to carnitine which i ...

All-trans retinoic acid Tretinoin, also known as all-''trans'' retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia. For acne, it is applied to the skin as a cream, gel or ointment. For leukemia, it is taken by mouth f ...

Amifostine Amifostine (ethiofos) is a cytoprotective adjuvant used in cancer chemotherapy and radiotherapy involving DNA-binding chemotherapeutic agents. It is marketed by Clinigen Group under the trade name Ethyol. Indications Amifostine is used therapeu ...

Amitriptyline Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat cyclic vomiting syndrome (CVS), major depressive disorder and a variety of pain syndromes from neuropathic pain to fibromyalgi ...

* Calcium magnesium *

Cannabinoid Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...

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Diethyldithiocarbamate Sodium diethyldithiocarbamate is the organosulfur compound with the formula NaS2CN(C2H5)2. It is a pale yellow, water soluble salt. Preparation This salt is obtained by treating carbon disulfide with diethylamine in the presence of sodium hydro ...

Glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

Glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, ...

Glutathione Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pero ...

Metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. ...

Minocycline Minocycline, sold under the brand name Minocin among others, is a tetracycline antibiotic medication used to treat a number of bacterial infections such as pneumonia. It is generally less preferred than the tetracycline doxycycline. It is also ...

N-acetylcysteine Acetylcysteine, also known as ''N''-acetylcysteine (NAC), is a medication that is used to treat paracetamol overdose and to loosen thick mucus in individuals with chronic bronchopulmonary disorders like pneumonia and bronchitis. It has been used ...

Nimodipine Nimodipine, sold under the brand name Nimotop among others, is calcium channel blocker used in preventing vasospasm secondary to subarachnoid hemorrhage (a form of cerebral hemorrhage). It was originally developed within the calcium channel ...

Omega-3 fatty acid Omega−3 fatty acids, also called Omega-3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chem ...

s * Org 2766 *

Oxcarbazepine Oxcarbazepine, sold under the brand name Trileptal among others, is a medication used to treat epilepsy. For epilepsy it is used for both focal seizures and generalized seizures. It has been used both alone and as add-on therapy in people with ...

Retinoic acid Retinoic acid (used simplified here for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that mediates the functions of vitamin A1 required for growth and development. All-''trans''-retinoic acid is required in ...

Venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic di ...

Vitamin B B vitamins are a class of water-soluble vitamins that play important roles in cell metabolism and synthesis of red blood cells. Though these vitamins share similar names (B1, B2, B3, etc.), they are chemically distinct compounds that often coexist ...

* Vitamin E

Treatment

A 2020 ASCO report provided an updated list of drugs tested and NOT recommended for treatment of CIPN. These recommendations are evidence-based, informed by randomized trials, and guided by expert clinical experience. * Gabapentin/pregabalin * Tricyclic antidepressants * Baclofen * Ketamine *

* Oral cannabinoids As of 2020, duloxetine is the only drug that is currently recommended to treat established CIPN. There are data from various clinical trials demonstrating that duloxetine decreases CIPN pain and other CIPN symptoms. However, it does not eliminate CIPN symptoms, and it can also have unwanted side effects such as dizziness, dry mouth, constipation, and diarrhea. It is not approved by the Food and Drug Association for treatment of CIPN.

Behavioral

There are promising and safe behavioral interventions for CIPN that have been suggested to be helpful based on randomized clinical trials: 1) stretching 2) walking 3) Strength training, resistance (strength) training 4) Balance (ability), balance exercises 5) yoga 6) meditation. Stretching, including nerve-gliding, is frequently included in a CIPN treatment plan to improve nerve excursion across joints, promote Axonal transport, axoplasmic flow, and decrease inflammation. Examples of stretching exercises for the neck and upper limbs include shoulder rolls, overhead arm reaches, and arm extensions. Examples of stretches for the lower body include lunges and hamstring pulls. Stretches like these have been clinically shown to help alleviate pain and restore at least some mobility in patients with CIPN. Walking can be effective in alleviating CIPN symptoms by boosting muscle power, increasing blood circulation, and improving balance. Walking provides low to moderately intense aerobic exercise (60-85% of heart rate reserve), and a regular walking schedule can decrease intensity and frequency of neuropathic symptoms while promoting healthy nerve growth and function. Resistance (strength) training has been tested in various clinical settings, and it has been shown to be helpful in treating CIPN symptoms such as temperature sensitivity, numbness, and tingling. By building muscle, strength training can improve a patient's ability to perform daily activities, improve balance, and reduce the risk of falling. Examples of strength training exercises include squats, overhead press, and calf raises. Balance exercises, such as tightrope exercises and hip flexion, are shown to be effective in reducing pain and improving quality of life for patients with CIPN. They are important in enhancing a patient's

, coordination, and preventing falls. Somatic yoga is often used by cancer survivors for symptom management, and it has been found to improve physical and mental health for patients with CIPN. Yoga combines movement, breathing exercises, and meditation to foster connection between the mind and body. Practice may decrease pain-associated stress and help a patient relax through modulation of the Neuroendocrinology, neuroendocrine system through the Hypothalamic–pituitary–adrenal axis, hypothalamic-pituitary-adrenal axis. Yoga's emphasis on dynamic movement can lead to improvement in flexibility, strength, balance, and stability, all of which may be negatively impacted by CIPN. Meditation helps to alleviate CIPN symptoms and CIPN-related stress by helping a patient relax and improve attention skills. By improving self-control and attention span, mediation helps to create emotional stability and enhances psycho-emotional balance. Despite the potential of these interventions, none of them have been shown to definitively help with CIPN as of the 2020 ASCO report. and therefore more research is needed.

Other therapeutics

Cryotherapy for patients with CIPN involves wearing frozen gloves and socks or ice packs to prevent and relieve symptoms. Various studies have been conducted to trial cryotherapy or cryocompression therapy, and their results are largely inconclusive. One study demonstrated that the development of CIPN symptoms were significantly delayed after the usage of cryotherapy. Another concluded that there was no significant difference between control groups receiving chemotherapy and treatment groups receiving cryotherapy in addition to chemotherapy. The second study's results did, however, support that frozen gloves improved some measures of patient-reported quality-of-life. Similarly, Cold compression therapy, compression therapy for patients with CIPN involves placing limbs in tight gloves or shoes. Studies testing compression therapy reported that sensory neuropathy was reduced in patients using tight surgical gloves. These studies are not conclusive, and additional randomized trials investigating the efficacy of cryotherapy and compression therapy for prevention and treatment of CIPN are ongoing. No conclusive recommendations about either therapy can be made as of 2020, although the potential harms of both are believed to be low to moderate. Scrambler therapy is an electro-analgesia therapy that is designed to block the conduction of nerve fibers to produce an analgesic effect through Transcutaneous electrical nerve stimulation, transcutaneous electrical nerve stimulation (TENS). In other words, this therapy should interfere with (“scramble”) the pain signal transmission of neurons by replacing it with “non-pain” information. One randomized trial evaluating the success of scrambler therapy in alleviating CIPN symptoms found no significant differences between treatment and control groups (Smith et al. 2020). Another trial testing scrambler therapy with patients with CIPN found patient-reported neuropathy symptoms and quality-of-life to be improved from baseline status. As of 2020, no conclusive recommendations can be made for scrambler therapy, but its potential harm is believed to be low.

Current research

Various institutions, universities, and organizations have dedicated years to performing clinical trials and conducting research on CIPN. The scientific community has had multiple breakthroughs in the mechanisms, prevention, and treatment of CIPN. In 2017, the National Cancer Institute's Symptom Management and Health-Related Quality of Life Steering Committee convened a meeting of CIPN and oncology management experts in the Clinical Trials Planning Meeting to evaluate the state of current research and plan ahead for future investigation. The goals of the meeting included identification of optimal outcome measures to define the CIPN phenotype, establishment of parameters that guide the evaluation of clinically meaningful effects, the adoption of approaches for inclusion of translational and biomarker and/or genetic measures, and discussion of the next steps to implement ideas into future clinical trials. Some of the lessons and limitations they learned from conducting past CIPN research are that 1) there was insufficient collaboration between pre-clinical and clinical researchers 2) patient reported CIPN symptoms are more sensitive than clinician-based assessments 3) there is substantial heterogeneity in the forms of neuropathy manifested across different patients 4) there are promising and understudied behavioral interventions for CIPN that may appeal more to patients who do not want pharmacological treatments. Based on these lessons, the experts concluded that a multifaceted approach is needed to alleviate the burden of CIPN including more well-planned Phase II clinical research, phase II intervention clinical trials, more longitudinal studies on the risk factors of CIPN, and the development of research networks to connect work from different research facilities. Overall, more research is needed to advance understanding of CIPN etiology, risk assessment, development, and treatment (e.g. duloxetine, genetic targets, and exercise).

References

{{Medicine Chemotherapy Cancer Peripheral nervous system disorders